Novel benzothiazine and benzothiadiazine derivatives method for preparing same and pharmaceutical compositions containing same

ABSTRACT

Compounds of formula (I):  
                 
wherein: 
     R 1  represents aryl or heteroaryl,    R 2  represents hydrogen, halogen or hydroxy,    A represents CR 4 R 5  or NR 4 ,    R 3  represents hydrogen, alkyl or cycloalkyl,    R 4  represents hydrogen or alkyl, or    A represents nitrogen and, together with adjacent —CHR 3 —, forms the ring  
                 
wherein m represents 1, 2 or 3,    R 5  represents hydrogen or halogen, their isomers and also their addition salts. Medicaments.

The present invention relates to new benzothiazine and benzothiadiazinecompounds, to a process for their preparation and to pharmaceuticalcompositions containing them.

It is now recognised that excitatory amino acids and, more especially,glutamate, play a crucial role in the physiological processes ofneuronal plasticity and in the mechanisms underlying learning andmemory. Pathophysiological studies have shown clearly that a deficiencyin glutamatergic neurotransmission is closely associated with thedevelopment of Alzheimer's disease (Neuroscience and Biobehavioralreviews, 1992, 16, 13-24; Progress in Neurobiology, 1992, 39, 517-545).

Moreover, numerous studies over recent years have demonstrated theexistence of excitatory amino acid receptor sub-types and theirfunctional interactions (Molecular Neuropharmacology, 1992, 2, 15-31).

Among those receptors, the AMPA(“α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid”) receptorappears to be the receptor most implicated in the phenomena ofphysiological neuronal excitability and especially in those phenomenaimplicated in the processes of memorisation. For example, learning hasbeen shown to be associated with an increase in the binding of AMPA toits receptor in the hippocampus, one of the cerebral regions essentialto mnemocognitive processes. Similarly, nootropic agents, such asaniracetam, have very recently been described as modulating positivelythe AMPA receptors of neuronal cells (Journal of Neurochemistry, 1992,58, 1199-1204).

In the literature, compounds of benzamide structure have been describedas having that same mechanism of action and as improving mnesicperformance (Synapse, 1993, 15, 326-329). Compound BA 74, in particular,is the most active of those new pharmacological agents.

Finally, patent specification EP 692 484 describes a benzothiadiazinecompound having a facilitatory action on AMPA flux and patentapplication WO 99/42456 describes, inter alia, a number ofbenzothiadiazine compounds as modulators of AMPA receptors.

In addition to being new, the benzothiazine and benzothiadiazinecompounds forming the subject-matter of the present inventionsurprisingly exhibit pharmacological activities in respect of AMPA fluxthat are clearly superior to those of the compounds of similar structuredescribed in the prior art. They are useful as AMPA modulators in thetreatment or prevention of mnemocognitive disorders associated with age,with anxiety or depressive syndromes, with progressive neurogenerativediseases, with Alzheimer's disease, with Pick's disease, withHuntington's chorea, with schizophrenia, with sequelae of acuteneurodegenerative diseases, with sequelae of ischaemia and with sequelaeof epilepsy.

The present invention relates more specifically to compounds of formula(I):

wherein:

-   R₁ represents an aryl or heteroaryl group,-   R₂ represents a hydrogen atom, a halogen atom or a hydroxy group,-   A represents a CR₄R₅ group or an NR₄ group,-   R₃ represents a hydrogen atom, a linear or branched (C₁-C₆)alkyl    group or a (C₃-C₇)cycloalkyl group,-   R₄ represents a hydrogen atom or a linear or branched (C₁-C₆)alkyl    group, or-   A represents a nitrogen atom and, together with the adjacent —CHR₃—    group, forms the ring    -   wherein m represents 1, 2 or 3,-   R₅ represents a hydrogen atom or a halogen atom,    to their isomers and to their addition salts with a pharmaceutically    acceptable acid or base, it being understood that:    -   “aryl group” is understood to mean an aromatic monocyclic group,        or a bicyclic group in which at least one of the rings is        aromatic, optionally substituted by one or more identical or        different groups: halogen, linear or branched (C₁-C₆)alkyl        (optionally substituted by one or more hydroxy groups), linear        or branched (C₁-C₆)alkoxy, linear or branched        (C₁-C₆)perhaloalkyl, linear or branched (C₁-C₆)alkoxycarbonyl,        linear or branched (C₁-C₆)alkylthio, carboxy, linear or branched        (C₁-C₆)acyl, linear or branched (C₁-C₆)perhaloalkoxy, hydroxy,        cyano, nitro, amino (optionally substituted by one or more        linear or branched (C₁-C₆)alkyl or linear or branched        (C₁-C₆)acyl groups), aminocarbonyl (optionally substituted by        one or more linear or branched (C₁-C₆)alkyl groups),        aminosulphonyl (optionally substituted by one or more linear or        branched (C₁-C₆)alkyl groups), mono- or        di-((C₁-C₆)alkylsulphonyl)amino, mono- or        di-(trifluoromethylsulphonyl)amino, PO(OR_(a))(OR_(b)) (wherein        R_(a), R_(b), which may be identical or different, represent a        hydrogen atom or a linear or branched (C₁-C₆)alkyl group),        benzyloxy, or phenyl (optionally substituted by one or more        identical or different groups: halogen, linear or branched        (C₁-C₆)alkyl, linear or branched (C₁-C₆)— perhaloalkyl, hydroxy        or linear or branched (C₁-C₆)alkoxy),    -   “heteroaryl group” is understood to mean an aromatic monocyclic        group, or a bicyclic group in which at least one of the rings is        aromatic, containing one, two or three identical or different        hetero atoms selected from nitrogen, oxygen and sulphur,        optionally substituted by one or more identical or different        groups: halogen, linear or branched (C₁-C₆)alkyl, linear or        branched (C₁-C₆)alkoxy, linear or branched (C₁-C₆)perhaloalkyl,        linear or branched (C₁-C₆)alkoxycarbonyl, carboxy, linear or        branched (C₁-C₆)acyl, linear or branched (C₁-C₆)perhaloalkoxy,        hydroxy, cyano, nitro, amino (optionally substituted by one or        more linear or branched (C₁-C₆)alkyl groups), aminosulphonyl        (optionally substituted by one or more linear or branched        (C₁-C₆)alkyl groups), or (C₁-C₆)alkylsulphonylamino.

Among the pharmaceutically acceptable acids there may be mentioned,without implying any limitation, hydrochloric acid, hydrobromic acid,sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid,lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid,fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid,methane-sulphonic acid, camphoric acid, etc.

Among the pharmaceutically acceptable bases there may be mentioned,without implying any limitation, sodium hydroxide, potassium hydroxide,triethylamine, tert-butylamine, etc.

The R₁O— group is preferably in position b of the phenyl carrying it.

The preferred R₁ group is an aryl group, especially optionallysubstituted phenyl.

When the aryl group is a substituted phenyl group, the substituent ispreferably in the meta position.

The preferred R₂ group is the hydrogen atom.

Preferred compounds of the invention are those wherein A represents anitrogen atom and, together with the adjacent —CHR₃— group, forms thering

wherein m represents 1, 2 or 3 and preferably 1.

Preferred compounds of the invention are:

-   7-(3-methylphenoxy)-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazine    5,5-dioxide,-   3-[(5,5-dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl)oxy]-benzoic    acid,-   3-(5,5-dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiazin-7-yl)oxy]-aniline,-   N-[3-(5,5-dioxido-2,3,3a,4-tetrahydro-1H-pyrrido[2,1-c][1,2,4]benzothiazin-7-yl)oxy]-phenyl]-methanesulphonamide,-   ethyl hydrogen    3-[(5,5-dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl)oxy]phenylphosphonate,    and their isomers.

The invention relates also to a process for the preparation of compoundsof formula (I).

The process for the preparation of compounds of formula (I) wherein Arepresents an NR₄ group or A represents a nitrogen atom and, togetherwith the adjacent CHR₃ group, forms the ring

wherein m represents 1, 2 or 3, is characterised in that there is usedas starting material a compound of formula (II):

wherein:

-   R′₁ represents a linear or branched (C₁-C₆)alkoxy group,-   R′₂ represents a hydrogen atom, a halogen atom or a linear or    branched (C₁-C₆)alkoxy group,    which is:-   (a) either reacted with the acid chloride of formula (III) in the    presence of a base, in a tetrahydrofuran or acetonitrile medium:    Cl—CH₂—(CH₂)_(m)—CH₂—COCl  (III),    wherein m is as defined for formula (I),    to yield the compound of formula (IV):    wherein R′₁ and R′₂ are as defined hereinbefore,    which is then cyclised in basic medium to yield the compound of    formula (V):    wherein R′₁, R′₂ and m are as defined hereinbefore,    which is subjected to reduction, in alcoholic or dimethylformamide    medium, in the presence of sodium borohydride, to yield the compound    of formula (VI):    wherein R′₁, R′₂ and m are as defined hereinbefore,    which is subjected to the action of boron tribromide    to yield the compound of formula (VII):    wherein R₂ and m are as defined hereinbefore,    (b) or cyclised    -   in the presence of an amidine of formula (VIII):        wherein:        R₃ is as defined for formula (I),        to yield the compound of formula (IX):        wherein R′₁, R′₂ and R′₃ are as defined hereinbefore,        which is:    -   either reduced with a metallic hydride        -   to yield the compound of formula (X):            wherein R′₁, R′₂, and R′₃ are as defined hereinbefore,    -   or alkylated by the action of a strong base in the presence of        an alkylating agent R′₄X wherein R′₄ represents a linear or        branched (C₁-C₆)alkyl group and X represents a halogen atom, and        then reduced        -   to yield the compound of formula (XI):            wherein R′₁, R′₂, R₃ and R′₄ are as defined hereinbefore, or    -   in the presence of an aldehyde of formula (XII):        wherein R₃ is as defined for formula (I),        to yield the compound of formula (X) described above,        the group R′₁ and the group R′₂, when it represents a linear or        branched (C₁-C₆)alkoxy group, of which compound of formula (X)        or (XI) are converted to hydroxy groups to yield the compound of        formula (XIII):        wherein R₂, R₃ and R₄ are as defined for formula (I),        which compound of formula (VII) or (XIII) is reacted with a        boronic acid compound of formula (XIV):        R₁B(OH)₂  (XIV),        wherein R₁ is as defined for formula (I),        to yield the compound of formula (I/a₁) or (I/a₂), particular        cases of the compounds of formula (I):        wherein R₁, R₂, R₃ and R₄ are as defined for formula (I),        wherein R₁, R₂ and m are as defined for formula (I),        which compounds of formula (I/a₁) or (I/a₂):        are subjected, if necessary, to conventional conversions in        respect of the substituents of the group R₁,        are, if necessary, purified according to a conventional        purification technique, are optionally separated into the        isomers according to a conventional separation technique and are        converted, if desired, into their addition salts with a        pharmaceutically acceptable acid or base.

The process for the preparation of compounds of formula (I) wherein Arepresents a CR₄R₅ group is characterised in that there is used asstarting material a compound of formula (XV):

wherein:

-   R′₁ represents a linear or branched (C₁-C₆)alkoxy group,-   R′₂ represents a hydrogen atom, a halogen atom or a linear or    branched (C₁-C₆)alkoxy group,    which is subjected to the action of chloroacetone in the presence of    dimethylformamide to yield the compound of formula (XVI):    wherein R′₁ and R′₂ are as defined hereinbefore,    which is subjected to rearrangement in basic medium to yield the    compound of formula (XVII):    wherein R′₁ and R′₂ are as defined hereinbefore,    which is deacetylated by heating at reflux in benzene medium in the    presence of an excess of ethylene glycol and a catalytic amount of    p-toluenesulphonic acid to yield the compound of formula (XVIII):    wherein R′₁ and R′₂ are as defined hereinbefore,    which is subjected to hydrolysis in acid medium to yield the    compound of formula (XIXa):    wherein R′₁ and R′₂ are as defined hereinbefore,    of which, optionally, according to the nature of the group R₃ it is    desired to obtain, the nitrogen atom is protected by a protecting    group, and which then, after treatment with a strong base, is    treated with a compound of formula R′₃—P,    wherein R′₃ represents a linear or branched (C₁-C₆)alkyl group or a    (C₃-C₇)cycloalkyl group and P represents a leaving group,    to yield, after deprotection of the nitrogen atom, the compound of    formula (XIX′a):    wherein R′₁, R′₂ and R′₃ are as defined hereinbefore,    which compound of formula (XIXa) or (XIX′a), represented by formula    (XIX):    wherein R′₁ and R′₂ have the same meaning and R₃ is as defined for    formula (I), is:    -   either subjected to catalytic reduction to yield the compound of        formula (XX):        wherein R′₁ and R′₂ are as defined hereinbefore,    -   or converted in alcohol by the action of a hydride the hydroxy        group of which is converted to a halogen atom by the action of        an appropriate reagent, to yield the compound of formula (XXI):        -   wherein R′₁ and R′₂ are as defined hereinbefore, R′₅            represents a halogen atom,    -   or subjected to the action of an organomagnesium compound R′₄        MgBr wherein R′₄ represents a linear or branched (C₁-C₆)alkyl        group,        to yield the compound of formula (XIXb):        wherein R′₁, R′₂ and R′₄ are as defined hereinbefore,        which compound of formula (XIXb):    -   is either subjected to catalytic reduction to yield the compound        of formula (XXII):        wherein R′₁, R′₂ and R′₄ are as defined hereinbefore,    -   or the hydroxy group of which is converted to a halogen atom by        the action of an appropriate reagent,        -   to yield the compound of formula (XXIII):            wherein R′₁, R′₂ and R′₄ are as defined hereinbefore and R′₅            represents a halogen atom,            the group R′₁ and the group R′₂, when it represents a linear            or branched (C₁-C₆)alkoxy group, of which compounds of            formulae (XX) to (XXIII) are converted to hydroxy groups to            yield the compound of formula (XXIV):            wherein R₂, R₄ and R₅ are as defined for formula (I),            which compound of formula (XXIV)            is reacted with a boronic acid compound of formula (XIV):            R₁B(OH)₂  (XIV),            wherein R₁ is as defined for formula (I),            to yield the compound of formula (I/b), a particular case of            the compounds of formula (I):            wherein R₁, R₂, R₃, R₄, R₅ are as defined for formula (I),            which compound of formula (I/b) is subjected, if necessary,            to conventional conversions in respect of the substituents            of the group R₁,            is purified, if necessary, according to a conventional            purification technique, is optionally separated into the            isomers according to a conventional separation technique and            is converted, if desired, into addition salts with a            pharmaceutically acceptable acid or base.

The invention extends also to pharmaceutical compositions comprising asactive ingredient a compound of formula (I) with one or more appropriateinert, non-toxic excipients. Among the pharmaceutical compositionsaccording to the invention there may be mentioned more especially thosewhich are suitable for oral, parenteral (intravenous or subcutaneous) ornasal administration, tablets or dragées, sublingual tablets, gelatincapsules, lozenges, suppositories, creams, ointments, dermal gels,injectable preparations, drinkable suspensions, etc. . . .

The dosage used can be adapted according to the nature and the severityof the disorder, the administration route and the age and weight of thepatient. The dosage ranges from 1 to 500 mg per day in one or moreadministrations.

The following Examples illustrate the invention but do not limit it inany way.

The starting materials used are known products or products preparedaccording to known procedures. The structures of the compounds describedin the Examples were determined according to customaryspectrophotometric techniques (infra-red, NMR, mass spectrometry . . .).

EXAMPLE 17-Phenoxy-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazine5,5-dioxide

Step A: N-[2-(Aminosulphonyl)-4-methoxyphenyl]-4-chlorobutanamide

144 mmol of triethylamine and then, dropwise, a solution containing 135mmol of 4-chlorobutanoic acid chloride in 30 ml of tetrahydrofuran(THF), are added to a solution containing 96.4 mmol of2-amino-5-methoxybenzenesulphonamide in 200 ml of THF. After stirringovernight at ambient temperature, the THF is evaporated off and theresidue is taken up in water. Following extraction with ethyl acetate,the organic phase is washed and dried. After evaporation, the expectedproduct is obtained in the form of an oil.

Step B:5,5-Dioxo-7-methoxy-2,3-dihydro-1H-Pyrrolo[2,1-c][1,2,4]benzothiadiazine

The product obtained in the above Step is stirred overnight at ambienttemperature in 320 ml of an aqueous 1N sodium hydroxide solution. Afterthe addition of 50 ml of ethyl acetate and stirring vigorously, theexpected product, which precipitates, is filtered off, rinsed and dried.

Step C:5,5-Dioxido-7-methoxy-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazine

106.5 mmol of sodium borohydride are added to a suspension containing35.5 mmol of the product obtained in the above Step in 40 ml ofdimethylformamide (DMF). After stirring overnight at ambienttemperature, the reaction mixture is cooled and then 150 ml of an icedsolution of 1N hydrochloric acid are added to the above mixture. Theexpected product precipitates and is filtered off.

Melting point: 193-198° C.

Step D:5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazin-7-ol

79.3 mmol of boron tribromide are added dropwise to a suspensioncontaining 26.7 mmol of the product obtained in the above Step in 350 mlof dichloromethane maintained at −60° C. under nitrogen. The temperatureis maintained for one hour and then the whole returns to ambienttemperature and is stirred overnight. After cooling the reaction mixturein an ice bath, 100 ml of water are added and the biphasic system formedis stirred vigorously. The suspension so formed is filtered. The whitesolid obtained is washed with water, with ether, and dried, yielding theexpected product.

Melting point: 237-242° C.

Step E:7-Phenoxy-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazine5,5-dioxide

A suspension containing 0.832 mmol of the compound obtained in the aboveStep, 1.66 mmol of phenylboronic acid, 1.25 mmol of copper acetate, 2.5mmol of pyridine and 100 mg of molecular sieve is stirred for 5 hours in20 ml of methylene chloride (CH₂Cl₂). After the addition of 20 ml ofCH₂Cl₂, the suspension is filtered. After evaporation of the filtrate,the residue is purified on a silica column, using as eluant a methylenechloride/ethyl acetate (95/5) mixture, and yields the expected product.

Melting point: 239-243° C. Elemental microanalysis: C % H % N % S %calculated 60.74 5.10 8.85 10.13 found 60.67 5.06 8.65 10.22

EXAMPLE 27-Phenoxy-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazine5,5-dioxide, a isomer EXAMPLE 37-Phenoxy-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazine5,5-dioxide, α Isomer

The compounds of Examples 2 and 3 are obtained by separation of theisomers of Example 1 on a chiral column, Chiralcel OC®, using as elutingsolvent a 1000/0.5 isopropanol/diethylamine mixture. After separation,each isomer is purified by chromatography on a silica column using aseluant a dichloromethane/ethyl acetate (20/10) mixture.

EXAMPLE 48-Phenoxy-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazine5,5-dioxide

The compound of the following Example was obtained according to theprocedure described in Example 1 using the appropriate startingmaterial.

Melting point: 184-187° C. Elemental microanalysis: C % H % N % S %calculated 60.74 5.10 8.85 10.14 found 60.24 5.04 8.69 10.09

The compounds of the following Examples were obtained according to theprocedure described in Example 1 using the appropriate boronic acids inStep E.

EXAMPLE 54-[(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl)oxy]benzonitrile

Melting point: 242-245° C. Elemental microanalysis: C % H % N % S %calculated 59.81 4.43 12.31 9.39 found 59.72 4.53 11.95 9.61

EXAMPLE 6 3-[(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl)oxy]benzonitrile

Melting point: 227-230° C. Elemental microanalysis: C % H % N % S %calculated 59.81 4.43 12.31 9.39 found 59.87 4.50 11.79 9.12

EXAMPLE 77-(4-Methylphenoxy)-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazine5,5-dioxide

Melting point: 222-226° C. Elemental microanalysis: C % H % N % S %calculated 61.80 5.49 8.48 9.70 found 61.77 5.54 8.29 9.38

EXAMPLE 87-(3-Methylphenoxy)-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazine5,5-dioxide

Melting point: 190-195° C. Elemental microanalysis: C % H % N % S %calculated 61.80 5.49 8.48 9.70 found 62.16 5.55 8.22 9.56

EXAMPLE 97-(4-Methoxyphenoxy)-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazine5,5-dioxide

Melting point: 188-191° C. Elemental microanalysis: C% H% N% S%calculated 58.94 5.24 8.09 9.26 found 59.11 5.35 7.90 9.43

EXAMPLE 107-(3-Methoxyphenoxy)-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4-benzothiadiazine5,5-dioxide Melting point: 152-155° C.

Elemental microanalysis: C % H % N % S % calculated 58.94 5.24 8.09 9.26found 59.06 5.37 7.75 9.12

EXAMPLE 117-(3-Methoxyphenoxy)-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazine5,5-dioxide, α Isomer EXAMPLE 127-(3-Methoxyphenoxy)-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazine5,5-dioxide, β Isomer

The compounds of Examples 11 and 12 were obtained by separation of thecompound of Example 10 on a chiral column under the same conditions asthose described for Examples 2 and 3.

EXAMPLE 137-(2-Methoxyphenoxy)-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazine5,5-dioxide

Melting point: 175-176° C. Elemental microanalysis: C % H % N % S %calculated 58.94 5.24 8.09 9.26 found 58.91 5.34 7.93 9.26

EXAMPLE 147-(3-Trifluoromethylphenoxy)-2,3,3a,4-tetrahydro-1H-pyrrolo-2,1-c][1,2,4]benzothiadiazine5,5-dioxide

Melting point: 195-197° C. Elemental microanalysis: C % H % N % S %calculated 53.12 3.93 7.29 8.34 found 53.31 4.05 7.20 8.22

The compounds of Examples 14a and 14b are obtained by separation of theenantiomers of Example 14 on a chiral column, Chiralcel OC®, under thesame conditions as those described for Examples 2 and 3.

EXAMPLE 14a7-(3-Trifluoromethylphenoxy)-2,3,3a,4-tetrahydro-1H-pyrrolo-[2,1-c][1,2,4]benzothiadiazine5,5-dioxide, α Isomer

Elemental microanalysis: C % H % N % S % calculated 53.12 3.93 7.29 8.34found 53.05 4.29 7.21 8.08

EXAMPLE 14b7-(3-Trifluoromethylphenoxy)-2,3,3a,4-tetrahydro-1H-pyrrolo-[2,1-c][1,2,4]benzothiadiazine5,5-dioxide, β Isomer

Elemental microanalysis: C % H % N % S % calculated 53.12 3.93 7.29 8.34found 53.24 4.19 7.28 8.12

EXAMPLE 157-(3-Nitrophenoxy)-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazine5,5-dioxide

Melting point: 201-204° C. Elemental microanalysis: C % H % N % S %calculated 53.18 4.18 11.63 8.87 found 53.53 4.23 11.36 8.80

EXAMPLE 167-[3,5-Di(trifluoromethyl)phenoxy]-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazine5,5-dioxide

Melting point: 201-203° C. Elemental microanalysis: C % H % N % S %calculated 47.79 3.12 6.19 7.09 found 47.90 3.24 6.10 7.07

EXAMPLE 17-(3-Chlorophenoxy)-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazine5,5-dioxide

Melting point: 194-198° C. Elemental microanalysis: C % H % N % S % Cl %calculated 54.78 4.31 7.99 9.14 10.11 found 54.92 4.36 7.91 9.15 10.95

EXAMPLE 187-(3-Ethoxyphenoxy)-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazine5,5-dioxide

Melting point: 150° C. Elemental microanalysis: C % H % N % S %calculated 59.98 5.59 7.77 8.90 found 60.11 5.64 7.56 8.61

EXAMPLE 197-(3-Trifluoromethoxyphenoxy)-2,3,3a,4-tetrahydro-1H-pyrrolo-[2,1-c][1,2,4]benzothiadiazine5,5-dioxide

Melting point: 175° C. Elemental microanalysis: C % H % N % S %calculated 51.00 3.78 7.00 8.01 found 51.10 3.82 6.93 8.10

EXAMPLE 207-(1-Naphthyloxy)-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazine5,5-dioxide

Melting point: 227-229° C. Elemental microanalysis: C % H % N % S %calculated 65.56 4.95 7.64 8.75 found 65.29 5.11 7.37 8.42

EXAMPLE 217-(2-Naphthyloxy)-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazine5,5-dioxide

Melting point: 234-236° C. Elemental microanalysis: C % H % N % S %calculated 65.56 4.95 7.64 8.75 found 65.31 4.95 7.44 8.66

EXAMPLE 227-(3-Benzyloxyphenoxy)-2,3,3a,4-tetrahydro-1H-pyrrolo-[2,1-c][1,2,4]benzothiadiazine5,5-dioxide

Melting point: 179-182° C. Elemental microanalysis: C % H % N % S %calculated 65.38 5.25 6.63 7.59 found 65.55 5.24 6.52 7.25

EXAMPLE 23 4-[(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazin-7-yl)oxy]phenyl

The expected product is obtained starting from the compound described inExample 9. There is added to that, after dissolution in methylenechloride and cooling in an ice bath, a solution of boron tribromide (1M)in CH₂Cl₂. After returning to ambient temperature and stirringovernight, the mixture is cooled in an ice bath. Following the additionof water, extraction with CH₂Cl₂, drying and evaporation, the expectedproduct is obtained after filtering off the residue and taking up inether and filtering.

Melting point: 175-178° C. Elemental microanalysis: C % H % N % S %calculated 57.82 4.85 8.43 9.65 found 57.66 4.83 8.18 9.63

EXAMPLE 243-[(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazin-7-yl)oxy]phenyl

The expected product is obtained by hydrogenation under atmosphericpressure at ambient temperature, for 5 hours, of 100 mg of the productof Example 22 in the presence of 20 mg of palladium/C in 20 ml ofethanol and 10 μl of concentrated hydrochloric acid. Followingfiltration and evaporation, the residue is taken up in ether and yieldsthe expected product after filtration.

Melting point: 205-208° C. Elemental microanalysis: C % H % N % S %calculated 57.82 4.85 8.43 9.65 found 57.80 4.89 8.27 9.31

EXAMPLE 25{3-[(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazin-7-yl)oxy]phenyl}ethanone

Melting point: 170-172° C. Elemental microanalysis: C % H % N % S %calculated 60.32 5.06 7.82 8.95 found 60.52 5.24 7.71 8.91

EXAMPLE 26 Methyl3-[(5,5-dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazin-7-yl)oxy]benzoate

Melting point: 223-227° C. Elemental microanalysis: C % H % N % S %calculated 57.74 4.85 7.48 8.56 found 57.49 5.02 7.31 8.37

EXAMPLE 273-[(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl)oxy]benzoicAcid

300 mg of the product of Example 26 are suspended in 5 ml of 1N NaOH.After stirring at reflux for one hour and acidification with 1Nhydrochloric acid, the expected product is obtained after filtration.

Melting point: 271-274° C. Elemental microanalysis: C% H% N% S%calculated 56.66 4.47 7.77 8.90 found 56.58 4.68 7.70 8.84

EXAMPLE 28 4-Methyl-7-phenoxy-3,4-dihydro-2H-1,2,4-benzothiadiazine1,1-dioxide

Step A: 7-Methoxy-4H-1,2,4-benzothiadiazine 1,1-dioxide

There is stirred for 1 night at 80° C. a suspension of 3.0 g of2-amino-5-methoxybenzene-sulphonamide in the presence of 1.31 g offormamidine hydrochloride and 2.27 ml of triethylamine in 50 ml oftoluene. The toluene is evaporated off in vacuo. The residue is taken upin water and the precipitate is filtered off.

Melting point: 253-257° C.

Step B: 7-Methoxy-4-methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide

2.88 g of the product obtained in the above Step are added portion byportion to a suspension of 9 ml of DMF containing 570 mg of 60% NaH inmineral oil. The mixture is stirred for 30 min. until a black solutionis obtained. 929 μl of iodomethane are then added dropwise thereto.Stirring is continued for 1 h and the reaction mixture is precipitatedby adding water. The precipitate is filtered off and rinsed with waterand then with ether to yield the expected product.

Melting point: 205-209° C.

Step C: 7-Methoxy-4-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine1,1-dioxide

1.19 g of sodium borohydride is added to a suspension of 2.37 g of theproduct of the above Step in 40 ml of ethanol. The mixture graduallybecomes homogeneous. After reaction for 1 h at ambient temperature, themixture is cooled in an ice bath and neutralised by the addition of 1NHCl. The white precipitate is stirred for 15 min. and the title productis filtered off.

Melting point: 126-128° C.

Step D: 4-Methyl-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-ol 1,1-dioxide

79.3 mmol of boron tribromide are added dropwise to a suspensioncontaining 2 g of the product obtained in the above Step in 200 ml ofdichloromethane maintained at −60° C. under nitrogen. The temperature ismaintained for one hour and then the whole returns to ambienttemperature and is stirred overnight. After cooling the reaction mixturein an ice bath, 100 ml of water are added and the biphasic system isstirred vigorously. The suspension so formed is filtered. The solidobtained is washed with water, with ether, and dried, yielding theexpected product.

Melting point: 168-172° C.

Step E: 4-Methyl-7-phenoxy-3,4-dihydro-2H-1,2,4-benzothiadiazine1,1-dioxide

The expected product is obtained according to the procedure described inStep E of Example 1, starting from the compound described in the aboveStep.

Melting point: 141-145° C. Elemental microanalysis: C % H % N % S %calculated 57.92 4.86 9.65 11.04 found 57.97 4.95 9.45 11.36

The compounds of Examples 29 to 32 were obtained according to theprocedure described for Example 28 using appropriate starting materials.

EXAMPLE 29 4-Ethyl-7-phenoxy-3,4-dihydro-2H-1,2,4-benzothiadiazine1,1-dioxide

Melting point: 179-181° C. Elemental microanalysis: C % H % N % S %calculated 59.19 5.30 9.20 10.53 found 59.00 5.31 9.07 10.53

EXAMPLE 30 4-Propyl-7-phenoxy-3,4-dihydro-2H-1,2,4-benzothiadiazine1,1-dioxide

Melting point: 143-145° C. Elemental microanalysis: C % H % N % S %calculated 60.36 5.70 8.80 10.07 found 60.75 5.74 8.62 10.15

EXAMPLE 313-[(4-Ethyl-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-yl)oxy]benzonitrile

Melting point: 143-146° C. Elemental microanalysis: C % H % N % S %calculated 58.34 4.59 12.76 9.74 found 58.71 4.68 12.44 9.49

EXAMPLE 324-Ethyl-7-(3-methoxyphenoxy)-3,4-dihydro-2H-1,2,4-benzothiadiazine1,1-dioxide

Melting point: 91-93° C. Elemental microanalysis: C % H % N % S %calculated 57.47 5.43 8.38 9.59 found 57.17 5.40 8.01 9.41

EXAMPLE 33 7-Phenoxy-3,4-dihydro-2H-1,2-benzothiazine 1,1-dioxide

Step A: 6-Methoxy-2-(2-oxopropyl)-1,2-benzisothiazol-3(2H)-one1,1-dioxide

360 mg of 6-methoxy-1,1-dioxo-1,2-dihydro-benzo[d]isothiazol-3-one areadded in small portions to a suspension of 72 mg of 60% NaH in mineraloil in 1.6 ml of anhydrous dimethylformamide. After stirring for 30 min.at ambient temperature, the reaction mixture becomes homogeneous and 162μl of chloroacetone are added thereto. The reaction mixture is heated at110° C. for 30 min. It is allowed to return to ambient temperature, andthen the mixture is precipitated by addition of water. The precipitateis filtered off, rinsed several times with water, suction-filtered offand dried in vacuo.

Melting point: 185-191° C.

Step B: 2-Acetyl-7-methoxy-2H-1,2-benzothiazin-4-ol 1,1-dioxide

A solution of sodium ethanolate in ethanol is prepared by dissolving1.08 g of sodium in 23 ml of ethanol at reflux. The temperature of thesolution is brought to 40° C. and 6.30 g of the product of Step A areadded thereto with stirring. The reaction mixture becomes thicker. 5 mlof ethanol are added to allow stirring to be carried out, and heatingfor an additional 10 min. is carried out at 50-55° C. The reactionmixture is then cooled in an ice bath and acidified with 3N HCl and theyellow precipitate formed is filtered off.

Melting point: 162-166° C.

Step C: 7-Methoxy-2,3-dihydro-4H-1,2-benzothiazine-4,4-ethylenedioxy1,1-dioxide

5.35 g of the product obtained in the above Step, 200 mg ofpara-toluenesulphonic acid and 5.6 ml of ethylene glycol are stirred atreflux in 200 ml of benzene in a round-bottomed flask on which aDean-Stark apparatus is mounted. After refluxing for 72 h, the benzeneis evaporated off in vacuo. The residue is dissolved in ethyl acetateand the organic phase is washed with water and then with saturated NaCl.Drying, filtration and evaporation are carried out and an oil isobtained which is crystallised from an ethyl ether/isopropyl ethermixture.

Melting point: 100-110° C.

Step D: 7-Methoxy-2,3-dihydro-4H-1,2-benzothiazin-4-one 1,1-dioxide

A solution of 2.63 g of the product of the above Step in a mixture of 50ml of methanol and 50 ml of 3N HCl is stirred at reflux for 15 min. Themethanol is evaporated off in vacuo and the aqueous phase is extractedwith ether. The organic phase is dried and treated with animal black.Following filtration and evaporation, the residue is taken up inisopropyl ether and the solid is filtered off.

Melting point: 124-127° C.

Step E: 7-Methoxy-3,4-dihydro-2H-1,2-benzothiazine 1,1-dioxide

1.77 g of the product of the above Step in 40 ml of acetic acid ishydrogenated under 5 bar at 70° C. in the presence of 1.75 g of 10%Pd/C. The mixture is allowed to return to ambient temperature and thecatalyst is filtered off. The filtrate is evaporated to dryness and theresidue is chromatographed on silica, using a 95/5 methylenechloride/ethyl acetate system as eluant, to yield the expected product.

Melting point: 144-145° C.

Step F: 3,4-Dihydro-2H-1,2-benzothiazin-7-ol 1,1-dioxide

14.1 ml of a 1M solution of BBr₃ in methylene chloride are addeddropwise to a solution of 1 g of the product of the above Step in 45 mlof methylene chloride cooled to −35° C. The mixture is allowed to returnto ambient temperature. After stirring for 3 h at ambient temperature,the reaction mixture is poured into water at 5° C. and extraction iscarried out with ethyl acetate. The organic phases are combined, washedwith saturated NaCl, dried, filtered and evaporated. A solid is obtainedwhich is taken up in a small amount of isopropyl ether. The titleproduct is filtered off.

Melting point: 173-177° C.

Step G: 7-Phenoxy-3,4-dihydro-2H-1,2-benzothiazine 1,1-dioxide

Starting from the compound described in the above Step, the expectedproduct is obtained according to the procedure described in Step E ofExample 1.

Melting point: 129-132° C. Elemental microanalysis: C % H % N % S %calculated 61.07 4.76 5.09 11.65 found 61.40 4.85 5.11 11.40

The compounds of Examples 34 to 38 were obtained according to theprocedure described in Example 1, using the appropriate arylboronic acidin Step E.

EXAMPLE 347-(3-Methylsulphanylphenoxy)-2,3,3a,4-tetrahydro-1H-pyrrolo-[2,1-c][1,2,4]benzothiadiazine5,5-dioxide

Melting point: 160° C. Elemental microanalysis: C % H % N % S %calculated 56.33 5.01 7.73 17.69 found 56.33 4.93 7.77 17.83

EXAMPLE 35 7-(3-Ethylphenoxy)-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazine 5,5-dioxide

Melting point: 143-144° C. Elemental microanalysis: C % H % N % S %calculated 62.77 5.85 8.13 9.31 found 62.69 5.88 8.1 9.26

EXAMPLE 367-(3-Isopropylphenoxy)-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazine5,5-dioxide

Melting point: 171-172° C. Elemental microanalysis: C % H % N % S %calculated 63.66 6.19 7.81 8.95 found 63.63 6.18 7.77 8.69

EXAMPLE 37 7-(3-Fluorophenoxy)-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazine 5,5-dioxide

Melting point: 201° C. Elemental microanalysis: C % H % N % S %calculated 57.47 4.52 8.38 9.59 found 57.06 4.51 8.15 9.63

EXAMPLE 387-(3-Bromophenoxy)-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazine5,5-dioxide

Melting point: 193-195° C. Elemental microanalysis: C % H % N % S % Br %calculated 48.62 3.82 7.09 8.11 20.21 found 48.95 3.82 7.03 8.13 20.02

EXAMPLE 39 3-[(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazin-7-yl)oxy]benzamide

A solution of 0.71 mmol of oxalyl chloride diluted with 1 ml of CH₂Cl₂is added dropwise to a suspension of 5 ml of CH₂Cl₂ and 10 μl of DMFcontaining 0.46 mmol of the acid obtained in Example 27. The whole isstirred for 1 h 30 at ambient temperature and evaporated to dryness. Inparallel, a solution of 5 ml of CH₂Cl₂ is saturated with ammonia, andthen the acid chloride obtained above dissolved in 3 ml of CH₂Cl₂ isadded dropwise thereto. After stirring for 2 h at ambient temperature,the reaction mixture is diluted with CH₂Cl₂ and the organic phase iswashed in succession with 1N HCl, water and saturated NaCl. After drying(MgSO₄) and removal of the solvent by evaporation, the residue istriturated in a mixture of isopropyl ether and ethyl ether. The whitesolid is filtered off to yield the expected product.

Melting point: 139-142° C. Elemental microanalysis: C % H % N % S %calculated 56.81 4.77 11.69 8.92 found 56.39 4.88 11.22 8.65

EXAMPLE 403-[(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazin-7-yl)oxy]-N,N-dimethylbenzamide

This compound is obtained according to the protocol of Example 39,replacing the ammonia with dimethylamine in the presence of pyridine.

Melting point: 199-202° C. Elemental microanalysis: C % H % N % S %calculated 58.9 5.46 10.85 8.28 found 58.97 5.54 10.66 7.86

EXAMPLE 413-[(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazin-7-yl)oxy]-N-methylbenzamide

This compound is obtained according to the protocol of Example 39,replacing the ammonia with methylamine in the presence of pyridine.

Melting point: 130-135° C. Elemental microanalysis: C % H % N % S %calculated 57.88 5.13 11.25 8.59 found 58.08 5.45 10.56 8.26

EXAMPLE 423-(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiazin-7-yl)oxy]aniline

The product of Example 15 (2.19 mmol) is dissolved in a mixture of 100ml of ethyl acetate and 50 ml of ethanol; 100 mg of 10%palladium-on-carbon are added and hydrogenation at atmospheric pressureis carried out for 1 h. The catalyst is filtered off, the filtrated isevaporated to dryness and the residue is precipitated from ether toyield the expected product after filtration.

Melting point: 221-226° C. Elemental microanalysis: C % H % N % S %calculated 57.99 5.17 12.68 9.68 found 57.90 5.28 12.44 9.59

EXAMPLE 43N-{3-[(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazin-7-yl)oxy]phenyl}-N-(methylsulphonyl)methane-sulphonamide

0.90 mmol of triethylamine, a spatula tip of DMAP and then, dropwise,0.90 mmol of methanesulphonic anhydride diluted with 8 ml of CH₂Cl₂, areadded to a solution of 0.45 mmol of amine of Example 42 in 30 ml ofCH₂Cl₂. After one night at ambient temperature, the reaction mixture iswashed (1N HCl, saturated NaCl), dried (MgSO₄). Purification of the 2products formed is carried out by chromatography on silica, eluting witha CH₂Cl₂ 100%→CH₂Cl₂/MeOH 95/5 gradient. The first product elutedcorresponds to the dimethylsulphonylated title product. The second,mono-methylsulphonylated compound corresponds to the product describedin the following Example.

Melting point: 214-215° C. Elemental microanalysis: C % H % N % S %calculated 44.34 4.34 8.62 19.73 found 44.72 4.55 8.55 19.84

EXAMPLE 44N-[3-(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrido[2,1-e][1,2,4]-benzothiazin-7-yl)oxy]phenyl]methanesulphonamide

As indicated in the above Example, the title product corresponds to thesecond product isolated by chromatography under the conditionsmentioned.

Melting point: 117-120° C. Elemental microanalysis: C % H % N % S %calculated 49.86 4.68 10.26 15.66 found 50.13 4.77 10.06 15.34

EXAMPLE 45 N-{3-[(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazin-7-yl)oxy]phenyl}ethanesulphonamide

This compound is obtained according to the procedure of Example 43,using the appropriate chlorosulphonyl.

Melting point: 169° C. Elemental microanalysis: C % H % N % S %calculated 51.05 5.00 9.92 15.14 found 50.9 4.97 9.87 15.00

EXAMPLE 46N-{3-[(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazin-7-yl)oxy]phenyl}propane-2-sulphonamide

This compound is obtained according to the procedure of Example 43,using the appropriate chlorosulphonyl.

Melting point: 179° C. Elemental microanalysis: C % H % N % S %calculated 52.16 5.30 9.60 14.66 found 51.88 5.33 9.87 14.71

EXAMPLE 47N-{3-[(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazin-7-yl)oxy]phenyl}benzenesulphonamide

This compound is obtained according to the procedure of Example 43,using the appropriate chlorosulphonyl.

Melting point: 142-145° C. Elemental microanalysis: C % H % N % S %calculated 56.04 4.49 8.91 13.60 found 56.33 4.62 8.60 13.67

EXAMPLE 48N-{3-[(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazin-7-yl)oxy]phenyl}acetamide

This compound is obtained according to the procedure of Example 43,using acetic anhydride.

Melting point: 251-253° C. Elemental microanalysis: C % H % N % S %calculated 57.89 5.13 11.25 8.59 found 58.16 5.18 11.09 8.48

EXAMPLE 493-[(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazin-7-yl)oxy]benzenesulphonamide

Step A:3-[(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl)oxy]benzenesulphonylChloride

A solution of 2 ml of glacial acetic acid and 340 μl of water issaturated with SO₂ by bubbling with SO₂ gas for 15 min. In parallel, at5° C. a solution of 1.51 mmol of the amine of Example 42 is prepared ina mixture of 1.3 ml of glacial acetic acid and 2.4 ml of concentratedHCl. A solution of 1.7 mmol of sodium nitrite dissolved beforehand in 1ml of water is added dropwise to that solution, and the reaction mixtureis stirred for 30 min. at 5° C. 0.6 mmol of CuCl₂.2H₂O is added to thesolution which has been saturated with SO₂ and the suspension obtainedis cooled to 5° C. The diazonium solution prepared above is addeddropwise to the latter. The mixture is stirred for 1 h at 5° C. and thenfor 1 h 30 while allowing to return to ambient temperature. The reactionmixture is poured onto ice and the precipitate is filtered off andrinsed with water. After drying, the expected product is obtained in theform of a beige powder.

Step B:3-[(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazin-7-yl)oxy]benzenesulphonamide

0.48 mmol of the product of the above Step A in a mixture of 10 ml of28% ammonium hydroxide, 2 ml of water and 1 ml of acetone is stirredovernight at ambient temperature. A slow transition to solution isobserved and, after one night, a turbid orange solution is obtained. Thesolution is poured into 1N HCl cooled beforehand in an ice bath. Theresulting suspension is stirred for 10 min. and the crude product isrecovered by filtration. Purification is carried out by chromatographyon silica using a 90/10 CH₂Cl₂/acetone mixture as eluant.

Melting point: 197-200° C. Elemental microanalysis: C % H % N % S %calculated 48.6 4.33 10.63 16.22 found 48.81 4.49 10.23 16.27

EXAMPLE 503-[(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazin-7-yl)oxy]-N-propylbenzenesulphonamide

This compound is obtained by reaction of the product of Step A ofExample 49 with the appropriate amine.

Melting point: 86-91° C. Elemental microanalysis: C % H % N % S %calculated 52.16 5.30 9.60 14.66 found 52.96 5.30 9.33 14.41

EXAMPLE 51 3-[(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazin-7-yl)oxy]-N-isopropylbenzenesulphonamide

This compound is obtained by reaction of the product of Step A ofExample 49 with, the appropriate amine.

Melting point: 151-155° C. Elemental microanalysis: C % H % N % S %calculated 52.16 5.30 9.60 14.66 found 52.41 5.50 9.68 14.66

EXAMPLE 52 Diethyl3-[(5,5-dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c[1,2,4]-benzothiadiazin-7-yl)oxy]phenylphosphonate

A mixture of 5.40 mmol of bromo compound of Example 38, 16.2 mmol ofdiethyl phosphite, 16.2 mmol of triethylamine, 1.62 mmol of Pd[P(Ph)₃]₄,is stirred overnight at 110° C. in 4 ml of DMF under a current ofnitrogen. The DMF is evaporated off, the residue is taken up in ethylacetate, and the organic phase is washed with a solution of 1N NaOH,water, saturated NaCl. After drying and evaporation in vacuo, a meringueis obtained which is crystallised from ether to yield the expectedproduct.

Melting point: 148-152° C. Elemental microanalysis: C % H % N % S %calculated 53.09 5.57 6.19 7.09 found 53.08 5.64 6.10 6.95

EXAMPLE 53 Ethyl hydrogen3-[(5,5-dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo-[2,1-c][1,2,4]benzothiadiazin-7-yl)oxy]phenylphosphonate

0.66 mmol of the product of Example 52 in 3 ml of 1N NaOH is stirred for8 h at 70° C. The reaction solution is acidified with 1N HCl and thewhite precipitate is filtered off to yield the expected product.

Melting point: 177-182° C. Elemental microanalysis: C % H % N % S %calculated 50.94 4.99 6.60 7.56 found 50.85 5.02 6.59 7.65

EXAMPLE 543-[(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazin-7-yl)oxy]phenylphosphonicAcid

Acetonitrile (20 ml), 0.66 mmol of the product of Example 52 and 1.98mmol of bromotrimethylsilane are stirred at reflux for 1 h. The solventand the excess of reagent are evaporated off in vacuo and the residue istaken up in solution in 10 ml of methanol. After stirring for 30 min.,the solution is evaporated to dryness and the residue is taken up in 1NHCl. A gum is obtained which is crystallised by adding a small amount ofCH₂Cl₂. The expected product is recovered by filtration.

Melting point: 166-169° C. Elemental microanalysis: C % H % N % S %calculated 48.49 4.32 7.07 8.09 found 48.34 4.29 7.00 8.06

EXAMPLE 55 7-(3-Methylphenoxy)-3,4-dihydro-2H-1,2-benzothiazine1,1-dioxide

Prepared by coupling the product obtained in Step F of Example 33 and3-methylphenylboronic acid according to the procedure described in StepE of Example 1.

Melting point: 116-118° C. Elemental microanalysis: C % H % N % S %calculated 62.26 5.23 4.84 11.08 found 62.69 5.17 4.94 10.90

The compounds of Examples 56 to 61 were obtained according to theprocedure described for Example 28 using ethyl iodide in Step B and theappropriate arylboronic acid in Step E.

EXAMPLE 564-Ethyl-7-[(3-methylsulphanyl)phenoxy]-3,4-dihydro-2H-[1,2,4]-benzothiadiazine1,1-dioxide

Melting point: 127-130° C. Elemental microanalysis: C % H % N % S %calculated 54.83 5.18 7.99 18.30 found 54.80 5.16 7.97 18.22

EXAMPLE 574-Ethyl-7-(3-methylphenoxy)-3,4-dihydro-2H-[1,2,4]benzothiadiazine1,1-dioxide

Melting point: 72-75° C. Elemental microanalysis: C % H % N % S %calculated 60.36 5.70 8.80 10.07 found 60.6 5.64 8.82 9.97

EXAMPLE 58N-{3-[(4-Ethyl-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-yl)oxy]phenyl}methanesulphonamide

Melting point: 165-168° C. Elemental microanalysis: C % H % N % S %calculated 48.35 4.82 10.57 16.13 found 48.74 5.02 10.39 16.22

EXAMPLE 591-{3-[(4-Ethyl-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-yl)oxy]phenyl}ethanone

Melting point: 164-166° C. Elemental microanalysis: C % H % N % S %calculated 58.94 5.24 8.09 9.26 found 59.06 5.24 7.81 8.88

EXAMPLE 60 Ethyl-7-(3-thienyloxy)-3,4-dihydro-2H-benzo[1,2,4]thiadiazine1,1-dioxide

Melting point: 152-154° C. Elemental microanalysis: C % H % N % S %calculated 50.30 4.55 9.03 20.66 found 50.26 4.42 8.92 20.97

EXAMPLE 617-(3,4-Dimethylphenoxy)-4-ethyl-3,4-dihydro-2H-1,2,4-benzothiadiazine1,1-dioxide

Melting point: 109-111° C. Elemental microanalysis: C % H % N % S %calculated 61.42 6.06 8.43 9.65 found 61.37 6.09 8.25 9.36

EXAMPLE 623-[(4-Ethyl-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-yl)oxy]aniline

This compound is obtained by reduction of the nitro product of Example15 according to the procedure described in Example 42.

Melting point: 128-132° C. Elemental microanalysis: C % H % N % S %calculated 56.41 5.37 13.16 10.04 found 56.84 5.53 12.89 10.17

EXAMPLE 63N-{3-[(4-Ethyl-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-yl)oxy]phenyl}-1,1,1-trifluoromethanesulphonamide

This compound is obtained by reaction of the amine of Example 62 withtrifluoromethanesulphonic anhydride under the conditions described inExample 43.

Melting point: 136-138° C. Elemental microanalysis: C % H % N % S %calculated 42.57 3.57 9.31 14.21 found 43.24 3.76 9.10 14.33

EXAMPLE 641-{3-[(4-Ethyl-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-yl)oxy]phenyl}ethanol

To 0.8 ml of anhydrous ethanol there are added in small portions 0.42mmol of NaBH₄ then 0.21 mmol of the product of Example 59. The solutionis stirred for 20 min. at ambient temperature. The reaction mixture iscooled in an ice bath and acidified by the dropswise addition of 1N HCl.The reaction mixture is extracted with ethyl acetate and the organicphase is washed (water, saturated NaCl), dried (MgSO₄) and evaporated toyield the expected product.

Melting point: 60° C. Elemental microanalysis: C % H % N % S %calculated 58.60 5.79 8.04 9.20 found 58.57 5.71 7.75 8.97

EXAMPLE 653-[(4-Ethyl-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-yl)oxy]benzoicAcid

This compound is obtained according to the procedure described inExample 27.

Melting point: 228-230° C. Elemental microanalysis: C % H % N % S %calculated 55.16 4.63 8.04 9.20 found 54.89 4.69 7.89 9.32

EXAMPLE 663-[(4-Ethyl-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-yl)oxy]benzamide

This compound is obtained by amidation of the product of Example 65according to the procedure of Example 39.

Melting point: 85-90° C. Elemental microanalysis: C % H % N % S %calculated 55.32 4.93 12.10 9.23 found 55.21 5.13 11.52 8.85

EXAMPLE 673-[(4-Ethyl-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-yl)oxy]-N,N-dimethylbenzamide

This compound is obtained by amidation of the product of Example 65according to the procedure of Example 40.

Melting point: 65-70° C. Elemental microanalysis: C % H % N % S %calculated 57.58 5.64 11.19 8.54 found 57.54 5.78 10.55 8.20

EXAMPLE 683-Phenoxy-6,6a,7,8,9,10-hexahydropyrido[2,1-c][1,2,4]benzothiadiazine5,5-dioxide

This compound is obtained according to the procedure described inExample 1 using 5-chloropropanoic acid chloride in Step A.

Melting point: 211-213° C. Elemental microanalysis: C % H % N % S %calculated 61.80 5.49 8.48 9.70 found 61.61 5.45 8.35 9.79

Pharmacological Study of the Products of the Invention

Study of the Excitatory Fluxes Induced by AMPA in Xenopus oocytes

a—Method:

mRNAs are prepared from cerebral cortex of male Wistar rat by theguanidinium thiocyanate/phenyl/chloroform method. The poly-(A⁺) mRNAsare isolated by chromatography on oligo-dT cellulose and injected in anamount of 50 ng per oocyte. The oocytes are left to incubate for 2 to 3days at 18° C. to allow expression of the receptors and are then storedat from 8 to 10° C.

Electrophysiological recording is carried out in a Plexiglass® chamberat from 20 to 24° C. in OR2 medium (J. Exp. Zool., 1973, 184, 321-334)by the 2-electrode “voltage-clamp” method, a 3rd electrode being placedin the bath to serve as reference.

All the compounds are administered via the incubation medium and theelectric current is measured at the end of the period of administration.AMPA is used at a concentration of 10 μM. For each compound studied, theconcentration that doubles (EC2X) or quintuples (EC5X) the intensity ofthe current induced by AMPA alone (5 to 50 nA) is determined.

b—Results:

The compounds of the invention potentiate very substantially theexcitatory effects of AMPA and their activity is very clearly superiorto that of the reference compounds. The compound of Example 3,especially, has an EC2X of 0.8 μM and a EC5X of 3.6 μM. As for thecompound of Example 29, it has an EC2X of 1.4 μM and an EC5X of 4.5 μM.PHARMACEUTICAL COMPOSITION Formulation for the preparation of 1000tablets each comprising 100 g a dose of 100 mg compound of Example 1hydroxypropyl cellulose  2 g wheat starch  10 g lactose 100 g magnesiumstearate  3 g talc  3 g

1-14. (canceled)
 15. A compound selected from those of formula (I):

wherein: R₁ represents aryl or heteroaryl, R₂ represents hydrogen,halogen or hydroxy, A represents CR₄R₅ or NR₄, R₃ represents hydrogen,linear or branched (C₁-C₆)alkyl or (C₃-C₇)cycloalkyl, R₄ representshydrogen or linear or branched (C₁-C₆)alkyl, or A represents nitrogenand, together with the adjacent —CHR₃— group, forms the ring

wherein m represents 1, 2 or 3, R₅ represents hydrogen or halogen, itsisomers and addition salts thereof with a pharmaceutically acceptableacid or base, it being understood that: “aryl” may be an aromaticmonocyclic group or a bicyclic group in which at least one of the ringsis aromatic, each of those groups being optionally substituted by one ormore identical or different halogen, linear or branched (C₁-C₆)alkyl(optionally substituted by one or more hydroxy groups), linear orbranched (C₁-C₆)alkoxy, linear or branched (C₁-C₆)perhaloalkyl, linearor branched (C₁-C₆)alkoxycarbonyl, linear or branched (C₁-C₆)alkylthio,carboxy, linear or branched (C₁-C₆)acyl, linear or branched(C₁-C₆)perhaloalkoxy, hydroxy, cyano, nitro, amino (optionallysubstituted by one or more linear or branched (C₁-C₆)alkyl or linear orbranched (C₁-C₆)acyl), aminocarbonyl (optionally substituted by one ormore linear or branched (C₁-C₆)alkyl), aminosulphonyl (optionallysubstituted by one or more linear or branched (C₁-C₆)alkyl), mono- ordi-((C₁-C₆)alkylsulphonyl)amino, mono- ordi-(trifluoromethylsulphonyl)amino, PO(OR_(a))(OR_(b)) (wherein R_(a),R_(b), which may be identical or different, represent hydrogen or linearor branched (C₁-C₆)alkyl), benzyloxy, or phenyl (optionally substitutedby one or more identical or different halogen, linear or branched(C₁-C₆)alkyl, linear or branched (C₁-C₆)perhaloalkyl, hydroxy or linearor branched (C₁-C₆)alkoxy), “heteroaryl” may be an aromatic monocyclicgroup, or a bicyclic group in which at least one of the rings isaromatic, containing one, two or three identical or different heteroatoms selected from nitrogen, oxygen and sulphur, each of those groupsbeing optionally substituted by one or more identical or differenthalogen, linear or branched (C₁-C₆)alkyl, linear or branched(C₁-C₆)alkoxy, linear or branched (C₁-C₆)perhaloalkyl, linear orbranched (C₁-C₆)alkoxycarbonyl, carboxy, linear or branched (C₁-C₆)acyl,linear or branched (C₁-C₆)perhaloalkoxy, hydroxy, cyano, nitro, amino(optionally substituted by one or more linear or branched (C₁-C₆)alkyl),aminosulphonyl (optionally substituted by one or more linear or branched(C₁-C₆)alkyl), or (C₁-C₆)alkylsulphonylamino.
 16. A compound of claim 15wherein R₂ represents hydrogen.
 17. A compound of claim 15 wherein theOR, group is in the b position of the phenyl ring carrying it.
 18. Acompound of claims 15 wherein R₁ represents optionally substitutedphenyl.
 19. A compound of claim 15 wherein A represents nitrogen and,together with the adjacent —CHR₃— group forms the ring

wherein m represents 1, 2 or
 3. 20. A compound of claim 19 wherein Arepresents nitrogen and, together with the adjacent —CHR₃— group formsthe ring

wherein m represents
 1. 21. A compound of claim 15 which is7-(3-methylphenoxy)-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazine5,5-dioxide, and its isomers.
 22. A compound of claim 15 which is3-[(5,5-dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl)oxy]benzoicacid, and its isomers.
 23. A compound of claim 15 which is3-(5,5-dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiazin-7-yl)oxy]aniline,and its isomers.
 24. A compound of claim 15 which isN-[3-(5,5-dioxido-2,3,3a,4-tetrahydro-1H-pyrrido[2,1-c][1,2,4]benzothiazin-7-yl)oxy]phenyl]methanesulphonamide,and its isomers.
 25. A compound of claim 15 which is ethyl hydrogen3-[(5,5-dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl)oxy]phenylphosphonate,and its isomers.
 26. A pharmaceutical composition useful in theprevention or treatment of diseases associated with AMPA flux comprisingas active principle an effective amount of a compound of claim 15,together with one or more pharmaceutically acceptable excipients orvehicles.
 27. A pharmaceutical composition useful in the prevention ortreatment of mnemocognitive disorders associated with age, anxiety ordepressive syndromes, neurodegenerative diseases, Alzheimer's diseases,Pick's diseases, Huntington's chorea, schizophrenia, sequelae of acuteneurodegenerative diseases, sequelae of ischemia and sequelae ofepilepsy comprising as active principle an effective amount of acompound of claim 15, together with one or more pharmaceuticallyacceptable excipients or vehicles.
 28. A method for treating a livinganimal body, including a human, afflicted with a condition associatedwith AMPA flux comprising the step of administering to the living animalbody, including a human, an amount of a compound of claim 15 which iseffective for alleviation of the condition.